Atopic dermatitis is a chronic disease manifesting eczema with pruritus that repeats aggravation and remission as a major lesion (see the Journal of Allergy and Clinical Immunology (J. Allergy Clin. Immunol), 1999, vol. 104, S123). While the symptom of atopic dermatitis is diverse and the cause of the disease has not been elucidated yet, it is suspected that various substances such as natural substances including ticks, fur, feather, bacteria and fungi, foods such as egg and milk, and synthetic products such as chemical fibers and detergents may act as antigens. It is pointed out that skin barrier dysfunction caused by dry skin plays an important role in atopic dermatitis. In addition, it is recently suggested that stress is related to the onset of atopic dermatitis.
Topical steroids are usually used as remedies of atopic dermatitis (the Journal of Allergy and Clinical Immunology (J. Allergy Clin. Immunol), 1999, vol. 104, S123). However, it is necessary to exactly select the kind of the external use steroid preparation depending on severity of the disease and application sites and timing, and the symptom is reported to be aggravated by misusage. Side effects such as skin atrophy and rosacea-like dermatitis are known to occur by long term dosage of the external use steroid preparation, and a phenomenon called as rebound by which skin symptoms are remarkably aggravated may occur when administration of the preparation is improperly suspended.
Histamine antagonists and antiallergic agents are used today as the remedies of atopic dermatitis other than the external use steroid preparations. While the histamine antagonist is useful in the sense of partly alleviation of itch, it is usually considered not to lead to improvement of the skin dermatitis. The antiallergic agents such as tranilast, ketotifen, oxatomide and azelastine hydrochloride are ineffective or have little effect against atopic dermatitis, if any, and are usually used as auxiliary measures today. While an ointment of tacrolimus as an immunosuppressant has been recently developed as a remedy of atopic dermatitis (the Journal of Allergy and Clinical Immunology (J. Allergy Clin. Immunol), 1999, vol. 104, S126), emergence of side effect such as strong irritation on the skin has been apprehended.
Chymase inhibitors and anti-IgE antibodies have been reported as new candidates against atopic dermatitis. For example, it was elucidated that the chymase inhibitors such as SUN C8257 (Laboratory Investigation (Lab Invest), 2002, vol 82, p 789; and International Archives of Allergy and Immunology (Int Arch Allergy Immunol), 2002, vol. 128, p 229) and Y-40613 (Japanese Journal of Pharmacology (Jpn J Pharmacol), 2002, vol. 90, p 214) exhibit effectiveness in various mouse dermatitis models. Chymase is a chymotrypsin-like enzyme released from mast cells, and is shown to relate to processing of a stem cell factor for mast cell's own proliferation (Proceedings of the National Academy of Science of the United State of the America (Proc Natl Acad Sci USA), 1997, vol. 94, p 9017; and Biochemical and Biophysical Research Communications (Biochem Biophys Res Commun), 2002, vol. 290, p 1478) and random migration of the eosinophils. Inhibitors of chymase are suggested to be potentially useful as remedies of atopic dermatitis (Journal of Leukocyte Biology (J Leukoc Biol), 2000, vol. 67, p 585; and Biochemical Pharmacology (Biochem Pharmacol), 2002, vol. 64, p 1187). The anti-IgE antibody suppressed binding of blood IgE to mast cells. An example of the anti-IgE antibody is omalizumab, which is in an advanced stage of the clinical test against bronchial asthma and is approved as a medicine. Since a degranulation reaction of the mast cell via IgE is conjectured to play an important role in atopic dermatitis, application of omalizumab to atopic dermatitis has been expected (Monaldi Archives for Chest Diseases (Monaldi Arch Chest Dis), 2003, vol. 59, p 25).
Now, in terms of the fact that there are no remedies of atopic dermatitis that are satisfactory in both beneficial effects and side effects, these drugs may be possibly used in the clinical practice.
While atopic dermatitis is usually diagnosed by appearance and distribution of eczema of the skin, emergence of pruritus, if any, and clinical history, IgE level in the blood, familial onset of the disease and complications such as bronchial asthma and allergic rhinitis, if any, may be basis of diagnosis (Japanese Dermatological Association: Guideline of Therapy of Atopic Dermatitis, Journal of Japanese Dermatological Association, 2004, vol. 114, p 135). Accordingly, medication of atopic dermatitis usually include selection of appropriate drugs (one or more drugs) from the external use steroid preparations, anti-histamine agents, anti-allergic agents and immunosuppressants depending on severity of the disease and administration of the drugs after diagnosis mainly by finding of appearance. However, the cause of onset of atopic dermatitis is not clear at present, and selection of the remedies are not always based on scientific reasons. Rather, it mainly depends on the experience of medical specialists. Since patients of atopic dermatitis include non-allergic type patients and intrinsic type patients who do not exhibit elevation of the blood IgE level, accurate diagnosis becomes more difficult.
Since atopic dermatitis is frequently familial origin, involvement of hereditary factors has been pointed out for a long time. When the disease is hereditary, specifying causative genes not only offer valuable information on the development of remedies specific to the disease but also are quite useful in terms of effective therapy based on gene diagnosis. For example, when a causative gene of the disease is identified to enable a substance that inhibits the function of a protein encoded by the causative gene to be obtained, the substance is naturally considered to be useful as a remedy for the disease. Investigation of the structure and expression level of the causative gene for individuals permits risk for the onset of the disease (readiness of morbidity) to be predicted while it is related to estimation of the effect (susceptibility) of the remedy that targets the causative gene. Therefore, ideal therapies in accordance with the causes of the disease of the individual may be expected to be possible.
A method usually called as linkage analysis is used for analyzing the causative gene of the disease, and this method has been already applied in atopic dermatitis. For example, Lee et al. have analyzed (genome-wide linkage study) in the entire region of the genome of patients of atopic dermatitis, and have reported that 3q21 of the chromosome is a candidate of the causative region (Nature Genetics (Nat Genet), 2000, vol. 26, p 470). Cookson's group has shown possibility of 1q21, 17q25 and 20p as candidates of the causative regions (Nature Genetics (Nat Genet), 2001, vol. 27, p 372). However, the gene region targetable by this method is restricted, and it is a current situation that no specific causative genes have been identified.
As for a method of targeting genes other than linkage analysis, there is a method in which the specific gene that may be the causes of the disease is subjected to Single nucleotide polymorphism (SNPs) analysis. SNPs analysis has been applied to chymase, high affinity IgE receptor (FcεRIβ, IL-4 receptor and RANTES with respect to atopic dermatitis, and correlation between the disease and onset thereof has been reported. For example, Mao et al. (Lancet, 1996, vol. 48, p 1) have reported SNPs of 3255th nucleotide of the human mast cell chymase gene is correlated with onset of atopic dermatitis, while Shirakawa et al. (Nature Genetics (Nat Genet), 1994, vol. 7, p 125) have reported SNPs of 1343rd nucleotide of the high affinity IgE receptor gene is correlated with onset of atopic dermatitis. However, correlation between SNPs of these genes and onset of atopic dermatitis is not always clear, and there are opposed reports that atopic dermatitis is not correlated at all in the SNPs analysis of the same gene (Human Heredity (Hum Hered), 1998, vol. 48, p 271; Human Heredity (Hum Hered), 2001, vol. 51, p 177; and International Archives of Allergy and Immunology (Int Arch Allergy and Immunol), 1996, vol. 111, p 44). Therefore, the causative genes of atopic dermatitis are not concluded to be identified today.